Clinical Findings: Sleep Architecture and Circadian Parameters

• Sleep Onset and Duration: Clinical studies in insomnia patients indicate that trazodone can modestly improve sleep initiation and maintenance. A recent meta-analysis found that trazodone (commonly 50–100 mg at bedtime) reduced sleep latency by about ~19 minutes on average and increased total sleep time, especially at higher doses (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports) (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports). Patients on trazodone had fewer awakenings and less time awake after sleep onset, reflecting improved sleep continuity (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports). However, some short-term trials did not show a large effect on time to fall asleep; the main benefits were in sleep maintenance and quality rather than dramatically faster sleep onset (Serotonin Receptors for Treatment of Insomnia).
• Sleep Stage Architecture: A consistent finding is that trazodone increases slow-wave sleep (deep N3 sleep). In healthy volunteers, a single night of trazodone significantly increased the amount of slow-wave (delta) sleep without reducing REM sleep (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed). Likewise, in insomnia patients, trazodone therapy was associated with a higher proportion of deep sleep and a reduction in light Stage 1 sleep (Serotonin Receptors for Treatment of Insomnia). Meta-analytic data confirm a significant increase in N3 slow-wave sleep (large effect size) with trazodone (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports). Importantly, trazodone tends to preserve REM sleep: unlike many antidepressants, it does not markedly suppress total REM duration. Studies report no significant change in REM sleep percentage or REM latency (time to first REM) with trazodone (Serotonin Receptors for Treatment of Insomnia). For example, a meta-analysis found virtually no difference in REM latency on trazodone vs. placebo (mean difference ~2 minutes, p = 0.88, i.e. no effect) (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports). This is in contrast to certain other antidepressants (e.g. SSRIs or TCAs) which often prolong REM latency and reduce REM sleep. Trazodone’s sleep benefit therefore comes from enriching restorative deep sleep and reducing awakenings, rather than altering REM physiology.
• Nocturnal Melatonin Secretion: Trazodone may enhance the body’s normal night-time melatonin rise. A small placebo-controlled trial reported that trazodone increased nocturnal melatonin levels without raising daytime melatonin, suggesting an amplification of the circadian night hormone signal (Trazodone Hypnotic Effect and Nocturnal Melatonin Secretion). In other words, patients had higher melatonin at night on trazodone, which could contribute to improved sleep and alignment of circadian phase. (By comparison, many SSRIs tend to blunt or dysregulate melatonin secretion.) This finding (Morera et al. 2009) implies trazodone might support the endogenous circadian mechanism that distinguishes night from day.
• Core Body Temperature Rhythm: Core body temperature normally follows a circadian cycle (with a nadir in the deep night). In a controlled trial on healthy young men, trazodone showed a trend toward advancing the timing of the minimum core body temperature (i.e. the nocturnal temperature trough occurred earlier) (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed). Specifically, trazodone slightly shifted the body temperature rhythm such that the lowest point happened somewhat sooner in the night, whereas another antidepressant (imipramine) in the same study did not change the phase of temperature (though it blunted the amplitude) (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed). An advance of the temperature nadir suggests a potential circadian phase-advancing effect of trazodone on the biological clock, at least in the short term. It’s worth noting that this effect was modest (“a tendency” in one study) and the overall 24-hour temperature cycle length was not changed (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed).
• Daytime Circadian Rhythms (Alertness/Sleepiness): There is evidence that nighttime trazodone can alter the timing of daytime sleepiness the next day. In one trial, researchers gave healthy volunteers trazodone at night and measured their propensity to fall asleep at various times the following day. They found that under placebo, the peak sleepiness occurred in the mid-morning (around 09:00), but after trazodone, the peak of sleepiness shifted later (around 11:00) ([Chronobiological research on antidepressant drugs: the effect of the antidepressant drugs, trazodone and imipramine on the circadian rhythm using electroencephalography in healthy volunteers] – PubMed). In other words, the normal morning dip in alertness was delayed by a couple of hours. The authors interpreted this as trazodone delaying the “day rhythm” of alertness ([Chronobiological research on antidepressant drugs: the effect of the antidepressant drugs, trazodone and imipramine on the circadian rhythm using electroencephalography in healthy volunteers] – PubMed). They attributed it partly to the drug’s effects on the previous night’s sleep – for example, because trazodone increased slow-wave sleep at night, subjects may have felt more refreshed in the early morning, pushing their sleepiness to later in the day ([Chronobiological research on antidepressant drugs: the effect of the antidepressant drugs, trazodone and imipramine on the circadian rhythm using electroencephalography in healthy volunteers] – PubMed). It’s an interesting finding that suggests trazodone can influence circadian phase markers of alertness, although it didn’t make people overall sleepier or more alert (total alertness was unchanged, just rescheduled) ([Chronobiological research on antidepressant drugs: the effect of the antidepressant drugs, trazodone and imipramine on the circadian rhythm using electroencephalography in healthy volunteers] – PubMed).
• Actigraphic Rest-Activity Rhythms: In patients with neurodegenerative disease (who often have blunted circadian cycles), trazodone has shown an ability to strengthen day–night activity patterns. A double-blind trial in Alzheimer’s disease (AD) patients with insomnia compared trazodone (50 mg at bedtime) to placebo. After 2 weeks, trazodone produced a significant increase in the relative amplitude of the rest-activity rhythm, indicating more robust differentiation between daytime activity and nocturnal rest (Circadian variables after two weeks with trazodone or placebo.  | Download Table). In practical terms, the actigraphy data showed that patients on trazodone had more consolidated nighttime sleep and more consistent daytime activity, effectively a more normal circadian pattern, compared to baseline/placebo (Circadian variables after two weeks with trazodone or placebo.  | Download Table). Other sleep parameters in that study improved as well (e.g. total sleep time and sleep efficiency increased on trazodone) (Circadian variables after two weeks with trazodone or placebo.  | Download Table). These findings suggest trazodone helped normalize the circadian rhythm in AD patients, who often suffer from fragmented day-night cycles. This is consistent with clinical observations that trazodone can help reduce sundowning and nighttime agitation in dementia by promoting a regular sleep-wake schedule.
• Delayed Sleep Phase Case: There is anecdotal and case-report evidence that trazodone can be used to adjust an abnormally delayed sleep phase. One case report described an elderly male with Delayed Sleep Phase Syndrome (DSPS) whose habitual sleep onset was around 5:00 AM. Treatment with trazodone 100 mg at night gradually advanced his sleep onset time by about 5 hours (from 5 AM to around midnight) over six weeks (Trazodone advanced a delayed sleep phase of an elderly male: A case report | Sleep and Biological Rhythms ). The authors noted that this patient had failed prior therapies like bright light, and hypothesized that trazodone “shifted the phase of the biological clock,” allowing his sleep-wake cycle to move earlier (Trazodone advanced a delayed sleep phase of an elderly male: A case report | Sleep and Biological Rhythms ). While this is a single-patient report, it demonstrates the potential for trazodone to facilitate a phase advance of the sleep schedule in someone with a severely delayed rhythm. The success was likely due to trazodone’s sleep-promoting effects enabling the patient to fall asleep at an earlier clock-time than his internal rhythm would normally permit.

Table: Selected Studies on Trazodone’s Effects on Sleep & Circadian Rhythms

Study (Population)	Design (Dose & Duration)	Key Outcomes
Nakamura et al. 2002 – Healthy volunteers​pubmed.ncbi.nlm.nih.gov​pubmed.ncbi.nlm.nih.gov	Single-blind crossover; Trazodone 100 mg/day for 3 days vs. placebo (11 young men)	↑ Slow-wave sleep; no change in REM sleep. Tendency to advance core body temperature nadir (earlier minimum)​pubmed.ncbi.nlm.nih.gov. Next-day peak sleepiness delayed by ~2 hours (daytime rhythm phase shift)​pubmed.ncbi.nlm.nih.gov. No overall increase in daytime sleepiness​pubmed.ncbi.nlm.nih.gov.
Zhou et al. 2022 – Insomnia patients (meta-analysis)​nature.com​nature.com	Pooled analysis of RCTs (various doses, 1–4 weeks)	Improved sleep continuity: ↓ awakenings and ↓ WASO (wake after sleep onset)​nature.com. ↑ N3 deep sleep (large increase)​nature.com. Slight ↓ sleep latency (~19 min)​nature.com. No significant effect on REM duration or REM latency​nature.com. Daytime sedation side-effect slightly higher than placebo in some studies​nature.com.
Grippe et al. 2015 – Alzheimer’s disease patients​researchgate.net	Double-blind placebo-controlled; Trazodone 50 mg at bedtime for 2 weeks (30 AD patients)	Stabilized circadian rhythm: ↑ relative amplitude of rest-activity cycle (more robust day/night pattern)​researchgate.net. ↑ Nocturnal sleep time and efficiency (actigraphy)​researchgate.net. Improved nighttime behavior (less sundowning reported). No serious adverse effects noted in this elderly group.
Nakase et al. 2005 – Delayed Sleep Phase Syndrome case​link.springer.com	Case report; Trazodone 100 mg nightly for 6 weeks (1 patient with DSPS)	Major phase advance: Sleep onset shifted ~5 hours earlier (from ~05:00 to 00:00) over 6 weeks​link.springer.com. Patient’s insomnia and daytime functioning improved with new schedule. Authors suggest trazodone realigned patient’s biological clock​link.springer.com.

(Abbreviations: RCT = randomized controlled trial; REM = rapid eye movement sleep; WASO = wake after sleep onset.)

Mechanisms of Trazodone in Circadian and Sleep Regulation

Trazodone’s pharmacological profile gives insight into how it influences sleep and circadian processes. It is a multifunctional agent: primarily a serotonin antagonist and reuptake inhibitor (SARI), with additional actions on other neurotransmitter receptors. Key aspects of its mechanism include:

• Serotonergic Receptors: Trazodone potently antagonizes the 5-HT₂A and 5-HT₂C serotonin receptors (Serotonin Receptors for Treatment of Insomnia). Blockade of 5-HT₂A in particular is believed to underlie its sleep-promoting and slow-wave sleep–enhancing effects. Normally, activation of 5-HT₂A/C by serotonin can fragment sleep and suppress deep sleep; by blocking these receptors, trazodone disinhibits the generation of slow-wave activity. This is similar to how certain other 5-HT₂ antagonists (e.g. mirtazapine or low-dose antipsychotics) also increase delta sleep. Notably, 5-HT₂A antagonism is achieved at relatively low trazodone doses (~25–100 mg) (Serotonin Receptors for Treatment of Insomnia), which explains why trazodone is effective as a hypnotic at doses much lower than those required for antidepressant action. Importantly, because trazodone blocks 5-HT₂ receptors (instead of stimulating them), it does not trigger the REM-suppressant effects typical of many SSRIs. This receptor profile helps preserve normal REM cycles, aligning with clinical findings that REM latency and duration are unchanged (Serotonin Receptors for Treatment of Insomnia).
• Serotonin Reuptake Inhibition: Trazodone weakly inhibits the serotonin transporter (SERT). At the low doses used for sleep (50–100 mg), its SERT inhibition is relatively modest (Serotonin Receptors for Treatment of Insomnia), but at higher doses (150–300 mg, used for depression) it becomes more significant. Increasing synaptic serotonin could potentially influence circadian rhythms, because the suprachiasmatic nucleus (SCN) – the body’s master clock – receives serotonergic input from the midbrain raphe. Serotonin in the SCN can modulate clock timing and light sensitivity via receptors like 5-HT₁A/₇ and 5-HT₂. While trazodone’s direct effect on the SCN in humans isn’t fully clear, its serotonergic activity may contribute to phase shifts. For instance, stimulation of 5-HT₇ receptors (not directly targeted by trazodone, but by increased serotonin) is known to affect the sleep–wake cycle (Serotonin Receptors for Treatment of Insomnia). Overall, by altering serotonin levels and blocking specific receptors, trazodone influences the neurotransmitter milieu that the circadian pacemaker and sleep centers experience.
• Histamine H₁ Antagonism: Trazodone is also a strong antihistamine at the H₁ receptor (Serotonin Receptors for Treatment of Insomnia). H₁ blockade causes sedation by inhibiting the wake-promoting actions of histamine in the brain. This contributes to trazodone’s ability to induce drowsiness and help initiate sleep. Histamine neurons in the hypothalamus fire during the day to promote wakefulness and are quiet at night; by blocking H₁ receptors, trazodone essentially amplifies the normal nighttime quieting of histamine’s alerting signal. The result is easier sleep onset and possibly a slight lowering of arousal threshold. Though H₁ antagonism doesn’t “shift” circadian phase per se, it facilitates sleep at the desired clock time, which can indirectly aid in circadian alignment (for example, helping someone with a delayed rhythm to fall asleep earlier than they normally would). Trazodone’s sedative effect occurs quickly (within 30–60 minutes of dosing), aligning well with using it at bedtime to reinforce the body’s nocturnal period.
• Adrenergic α₁ Antagonism: Another receptor trazodone blocks is the alpha-1 adrenergic receptor (Serotonin Receptors for Treatment of Insomnia). This action can cause a drop in blood pressure and contribute to relaxation and sedation. In terms of sleep, α₁ blockade may reduce norepinephrine-driven arousal. (The locus coeruleus, which releases norepinephrine, is part of the arousal system that is active in wake and less active in sleep.) By dampening α₁ activity, trazodone might promote a parasympathetic, “rest-and-digest” state conducive to sleep. There is no direct circadian phase shift from this effect, but it synergizes with H₁ blockade to consolidate sleep during the night.
• Effects on Melatonin and Circadian Hormones: Trazodone’s influence on serotonin and its receptors can have downstream effects on the pineal gland and melatonin production. Melatonin is synthesized from serotonin in the pineal gland at night. One hypothesis for the observed increase in nocturnal melatonin with trazodone (Trazodone Hypnotic Effect and Nocturnal Melatonin Secretion) is that by blocking 5-HT₂C receptors (and perhaps 5-HT₂A) in the pineal or elsewhere, trazodone removes inhibitory signals, thereby allowing more serotonin to be converted to melatonin. Alternatively, trazodone might enhance melatonin via indirect mechanisms, such as improving sleep (since endogenous melatonin secretion is enhanced during stable sleep in darkness). Regardless, the net effect is that trazodone augments the body’s own melatonin signal at night, potentially strengthening circadian night cues. Melatonin itself is a key hormone that feeds back on the circadian clock (through MT₁/MT₂ receptors in the SCN) to signal “it’s dark/nighttime.” By boosting melatonin, trazodone could reinforce the alignment of the internal clock to nighttime.
• Molecular Clock Gene Expression: Emerging research suggests that trazodone can act at a genomic level on circadian clock genes. A 2022 preclinical study examined rat brain tissue after chronic trazodone treatment and found significant changes in core clock gene expression in regions involved in mood and sleep regulation (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy) (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy). For example, chronic trazodone upregulated the mRNA levels of Bmal1 (a positive arm clock gene) and Period (Per1, Per2) genes in the prefrontal cortex and hippocampus, among other areas (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy) (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy). These genes are integral to the molecular circadian oscillator in cells. The findings imply that trazodone can entrain or modify the molecular clocks in the brain, perhaps as part of its therapeutic actions. Upregulating Bmal1/Per could strengthen circadian oscillations or shift their timing. It’s noteworthy that different brain regions showed different responses (e.g. nucleus accumbens clocks were downregulated) (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy) (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy), highlighting a complex picture. While these animal-model results need clinical correlation, they provide a mechanistic clue: trazodone’s pharmacology extends to the level of gene expression for clock components, which might help stabilize circadian rhythms in patients.
• Promotion of Sleep as a Circadian Synchronizer: By improving the depth and continuity of sleep, trazodone may secondarily assist circadian alignment. A consolidated night’s sleep is itself a zeitgeber (time-cue) for the body. Good sleep at the proper local night can help internal clocks in peripheral tissues synchronize. In conditions like Alzheimer’s or depression, where circadian disorganization is common, trazodone-induced sleep regularity can impose a stronger 24-hour rhythm on an otherwise erratic system (Circadian variables after two weeks with trazodone or placebo.  | Download Table). Essentially, sleep is the output of the circadian system, but also feeds back to it – and trazodone, by normalizing sleep, may feed back beneficially to the clock’s timing. This non-photic entrainment (through sleep and possibly mealtime alignment if a patient adjusts their routine) complements other measures like light exposure.

In summary, trazodone’s mechanism involves a constellation of neurotransmitter effects (serotonin, histamine, adrenergic) that converge on promoting night-time sleep and possibly interacting with circadian regulators. It doesn’t target the circadian clock in the direct manner that a true “chronobiotic” (like melatonin or light therapy) would, but it interfaces with the circadian system indirectly: by modulating serotonin (which the clock uses) and by consolidating the sleep that helps reset and maintain circadian rhythms.

Practical Use in Circadian Rhythm Disorders and Phase Shifts

1. Delayed Sleep Phase and Irregular Schedules: Trazodone has been explored as a tool to manage conditions like Delayed Sleep-Wake Phase Disorder (DSWPD), where patients struggle to fall asleep until very late. The sedative action of trazodone can help such individuals initiate sleep at an earlier clock time, effectively pushing their sleep phase earlier. The case report of an elderly DSPS patient advancing from a 5 AM bedtime to midnight with trazodone illustrates this application (Trazodone advanced a delayed sleep phase of an elderly male: A case report | Sleep and Biological Rhythms ). In clinical practice, some physicians use trazodone in combination with behavioral chronotherapy (like gradually earlier bedtimes and morning light) to anchor a new sleep schedule. By making the patient drowsy in the evening, trazodone can overcome the “second wind” alertness that people with delayed phase often experience at night. Over days to weeks, this can lead to a re-entrainment of their circadian rhythm to a more normal schedule, as seen in the above case. It is worth noting that melatonin at dusk is a first-line chronobiotic for DSWPD, but not everyone tolerates or responds to melatonin; trazodone offers an alternative or adjunct in resistant cases (Trazodone advanced a delayed sleep phase of an elderly male: A case report | Sleep and Biological Rhythms ).

2. Jet Lag: Jet lag is a transient circadian misalignment caused by rapid travel across time zones. The mainstay treatments for jet lag are timed light exposure and melatonin administration, which actively shift the circadian clock. Trazodone is not a primary treatment for jet lag, since it does not actively speed circadian re-synchronization. However, it can be used for symptomatic relief – specifically, to help travelers get sleep during the local night at the destination. Guidelines (e.g. CDC Yellow Book) suggest that a short-acting hypnotic can be considered to improve sleep quality on the first nights in a new time zone ([

Jet Lag | CDC Yellow Book 2024 ](https://wwwnc.cdc.gov/travel/yellowbook/2024/air-land-sea/jet-lag#:~:text=possible.%20Consider%20recommending%20short,lag%20during%20short%20round%20trips)). In this context, trazodone (taken at local bedtime) may help someone who is jet-lagged fall asleep even if their internal clock thinks it’s daytime. For example, a traveler who flies east may arrive with an internal evening occurring late at night local time; a dose of trazodone could counteract the wakefulness and allow sleep, thereby reducing insomnia symptoms of jet lag. This in turn can reduce next-day fatigue and aid functional recovery. Trazodone’s half-life (~6 hours) is intermediate, so one must be cautious about morning grogginess if taken too late at night. Importantly, while a sedative like trazodone can help cope with jet lag, it doesn’t realign circadian rhythms by itself. Travelers still need to adjust by light exposure and the passage of days. Thus, trazodone might be viewed as a short-term sleep aid for jet lag – useful to “knock out” for a night flight or the first night abroad – but it is not a substitute for chronobiotic therapy. No large clinical trials have specifically tested trazodone for jet lag prevention or treatment; recommendations are extrapolated from its general sleep-inducing properties and relative safety.

3. Shift Work Sleep Disorder: Shift workers (e.g. night shift or rotating shift workers) often experience circadian misalignment leading to insomnia when trying to sleep at odd hours and excessive sleepiness during work. The cornerstone treatments for shift work disorder include strategic light exposure (bright light at night, darkness in daytime) and wake-promoting agents for the work period, as well as melatonin to help daytime sleep in some cases. Trazodone is sometimes used off-label to assist shift workers in sleeping during their off-duty time (for instance, a night shift worker who needs to sleep in the morning or afternoon). As a sleep-promoting medication, trazodone can increase the likelihood of falling asleep in the daytime “biological night” for the worker. Some long-term night shift nurses report using low-dose trazodone nightly to maintain a sleep schedule despite an inverted day/night routine. The advantage of trazodone in this context is that it is non-addictive and can be used chronically, unlike benzodiazepines. However, there are important caveats: any sleep aid for shift work must be timed properly to avoid carryover sedation into the work shift. For example, if a shift worker takes trazodone after a night shift at 8 AM, they must allow sufficient duration of sleep and drug clearance before waking for the next shift (to avoid residual drowsiness or impaired alertness on the job). Guidelines acknowledge that prescription hypnotics (including agents like zolpidem or possibly sedating antidepressants) can be useful for shift workers to get needed sleep (What Treatments Are Available for Shift Work Disorder? | Sleep Foundation). These medications do not realign the circadian clock – they simply help the person sleep against their normal circadian drive. Thus, trazodone in shift work is a symptomatic treatment: it improves sleep duration and quality in an adverse circadian phase, which can in turn improve overall well-being and performance, but the underlying circadian misalignment remains. For persistent shift work disorder, combination approaches are best (light therapy, scheduled naps, caffeine at work, etc., with trazodone or similar for sleep as needed) (What Treatments Are Available for Shift Work Disorder? | Sleep Foundation) (What Treatments Are Available for Shift Work Disorder? | Sleep Foundation). One notable advantage is that trazodone enhances slow-wave sleep; shift workers often are sleep-deprived and slow-wave sleep is particularly restorative, so trazodone may help them feel more refreshed than they would from the same length of untreated sleep. Caution is advised in those who may already have sleep apnea (common in shift workers) because trazodone, like other sedatives, could worsen apnea in some cases (though some studies suggest trazodone doesn’t dramatically affect apnea index (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports)).

4. Circadian Rhythm Sleep Disorders in Dementia: Elderly patients with dementia frequently develop irregular sleep-wake patterns, with daytime napping and nighttime wakefulness (sometimes called irregular sleep-wake rhythm disorder). Low-dose trazodone is frequently prescribed in such cases to consolidate nighttime sleep. As discussed, a controlled trial in Alzheimer’s patients showed improvements in circadian rhythm robustness on trazodone (Circadian variables after two weeks with trazodone or placebo.  | Download Table). Patients had more pronounced day vs. night activity patterns, implying trazodone helped anchor their rhythms. Clinically, caregivers often report that trazodone at night leads to dementia patients being less restless at night and more awake during the day, effectively correcting a flipped schedule. This use positions trazodone as a gentler alternative to antipsychotics or benzodiazepines for managing sleep disturbances in dementia. It addresses circadian dysregulation by enforcing a strong sleep period at night, which in turn promotes a clearer wake period in the day. Given its relative safety in the elderly (especially compared to anticholinergics or benzos), trazodone is considered a viable option for long-term management of sleep-wake disturbances in Alzheimer’s and Parkinson’s disease patients (Circadian variables after two weeks with trazodone or placebo.  | Download Table). It does not universally work for every patient, but in some cases it can restore a near-normal 24-hour rhythm, greatly improving quality of life for both patients and caregivers.

5. Limitations and Considerations: While trazodone has these applications, it’s important to emphasize that it is not a dedicated chronotherapeutic agent. Unlike melatonin agonists (e.g. ramelteon, tasimelteon) that directly act on circadian clock receptors, trazodone’s effects on circadian timing are indirect. Its primary role is to improve sleep. Any circadian benefits (phase shifting or rhythm stabilization) are secondary consequences of improved sleep or serotonin modulation. Furthermore, formal guidelines (such as those by the American Academy of Sleep Medicine) do not list trazodone as a first-line treatment for circadian rhythm sleep disorders; rather, they caution that evidence for trazodone in primary insomnia is limited and it can have side effects (Common Sleep Disorders in Adults: Diagnosis and Management | AAFP) (Common Sleep Disorders in Adults: Diagnosis and Management | AAFP). Daytime drowsiness, orthostatic hypotension, and rarely, complex sleep behaviors or priapism are considerations. Therefore, when using trazodone for circadian-related issues, clinicians tailor it to the individual, often after trying standard chronobiotic measures. It can be very useful as part of a multi-modal strategy – for example, using light therapy in the morning and trazodone at night to correct a delayed phase.

In conclusion, trazodone meaningfully influences sleep-related processes that interact with circadian rhythms. Clinically it improves sleep continuity and depth, which can lead to better circadian alignment in conditions of dysrhythmia. Mechanistically, it engages serotonergic pathways (and possibly melatonin production) that link to the circadian clock. And in practice, while not a magic “phase shifter” on its own, trazodone has found a niche in managing difficult sleep schedule disorders such as delayed phase, shift work sleep problems, and dementia-related circadian disruption. Its ability to enhance restorative sleep without heavily suppressing REM or altering normal sleep stages makes it a unique tool, distinct from traditional hypnotics. Used thoughtfully, trazodone can thus support circadian health by doing what it does best – ensuring a good night’s sleep at the proper time.

Sources:

• Nakamura, Yamadera et al. (2002) – Healthy volunteer study showing trazodone increased deep sleep and tended to phase-shift temperature rhythm (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed) (Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature – PubMed).
• Suzuki et al. (2002) – Related study on volunteers, noting delayed daytime sleepiness rhythms with trazodone ([Chronobiological research on antidepressant drugs: the effect of the antidepressant drugs, trazodone and imipramine on the circadian rhythm using electroencephalography in healthy volunteers] – PubMed).
• Lee & Choo (2019) – Review of serotonin receptors in insomnia; notes trazodone (5-HT₂A antagonist) improves sleep architecture (↑SWS, no change in REM) (Serotonin Receptors for Treatment of Insomnia).
• Zhou et al. (2022) – Systematic review/meta-analysis of trazodone for insomnia: increased N3 sleep, reduced awakenings, minimal effect on REM sleep or latency (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports) (Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis | Scientific Reports).
• Morera et al. (2009) – Study indicating trazodone increases nocturnal melatonin levels (enhancing the circadian night signal) (Trazodone Hypnotic Effect and Nocturnal Melatonin Secretion).
• Carboni et al. (2022) – Rat study showing trazodone alters expression of clock genes (e.g. Bmal1, Per1/2) in brain regions (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy) (Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy).
• Camargos/Grippe et al. (2014–2015) – Trials in Alzheimer’s disease: trazodone improved sleep efficiency and normalized circadian activity rhythm amplitude (Circadian variables after two weeks with trazodone or placebo.  | Download Table).
• Nakase et al. (2005) – Case report of trazodone successfully treating delayed sleep phase syndrome by shifting sleep ~5 hours earlier (Trazodone advanced a delayed sleep phase of an elderly male: A case report | Sleep and Biological Rhythms ).
• CDC Yellow Book (2024) – Jet lag management guidelines; recommends short-acting hypnotics to maintain sleep on short trips​wwwnc.cdc.gov.

• Sleep Foundation (2022) – Shift Work Disorder advice; mentions prescription sleep aids can facilitate daytime sleep for shift workers (with caution) (What Treatments Are Available for Shift Work Disorder? | Sleep Foundation) (What Treatments Are Available for Shift Work Disorder? | Sleep Foundation).
• AASM/American Family Physician (2022) – Insomnia guidelines noting trazodone is not officially recommended as first-line (due to mixed risk-benefit) (Common Sleep Disorders in Adults: Diagnosis and Management | AAFP) (Common Sleep Disorders in Adults: Diagnosis and Management | AAFP), though it’s widely used off-label for sleep.